when the animals’ brain would normally begin
to clear A-beta. Compared with well-rested mice,
sleep-deprived animals developed more than
two times as many amyloid plaques over
about a month, Holtzman says.
He thinks Alzheimer’s disease is a
kind of garbage collection problem.
As nerve cells, or neurons, take care of
business, they tend to leave their trash
lying around. They throw away A-beta,
But sometimes, especially when
cheated on sleep, the brain doesn’t get the
chance to mop up all the A-beta that the neurons
produce, according to a developing consensus. A-beta starts to collect in the small seams
between cells of the brain, like litter in the gutter. If A-beta piles up too much, it can accumulate
into plaques that are thought to eventually lead
to other problems such as inflammation and the
buildup of tau, which appears to destroy neurons
and lead to Alzheimer’s disease.
About a decade ago, Holtzman wanted to know
if levels of A-beta in the fluid that bathes neurons fluctuated as mice ate, exercised, slept and
other wise did what mice do. It seemed like a run-of-the-mill question. To Holtzman’s surprise,
time of day mattered — a lot. A-beta levels were
highest when the animals were awake but fell
when the mice were sleeping (SN: 10/24/09, p. 11).
“We just stumbled across this,” Holtzman says.
Still, it wasn’t clear whether the difference was
related to the hour, or to sleep itself. So Holtzman
and colleagues designed an experiment in which
they used a drug to force mice to stay awake or
fall asleep. Sure enough, the A-beta levels in
the brain-bathing fluid rose and fell with sleep,
regardless of the time on the clock.
A-beta levels in deeply sleeping versus wide-awake mice differed by about 25 percent. That
may not sound like a dramatic drop, but over the
long term, “it definitely will influence the probability [that A-beta] will aggregate to form amyloid
plaques,” Holtzman says.
The study turned conventional thinking on its
head: Perhaps Alzheimer’s doesn’t just make it
hard to sleep. Perhaps interrupted sleep drives
the development of Alzheimer’s itself.
Published in Science in 2009, the paper triggered
a flood of research into sleep and Alzheimer’s.
While the initial experiment found that the condition worsens the longer animals are awake,
research since then has found that the reverse is
true, too, at least in flies and mice.
Using fruit flies genetically programmed to
mimic the neurological damage of Alzheimer’s
disease, a team led by researchers at Washington
University School of Medicine reversed the cognitive problems of the disease by simply forcing the
flies to sleep (SN: 5/16/15, p. 13).
Researchers from Germany and Israel
reported in 2015 in Nature Neuroscience that
slow-wave sleep — the deep sleep that occupies the brain most during a long snooze and is
thought to be involved in memory storage — was
disrupted in mice that had A-beta deposits in
their brains. When the mice were given low doses
of a sleep-inducing drug, the animals slept more
soundly and improved their memory and ability
to navigate a water maze.
Even with these studies in lab animals indicating that loss of sleep accelerates Alzheimer’s,
researchers still hesitate to say the same is true
in people. There’s too little data. Human studies
are harder and more complicated to do. One big
hurdle: The brain changes in humans that lead to
Alzheimer’s build up over decades. And you can’t
do a controlled experiment in people that forces
half of the study’s volunteers to endure years of
Plus the nagging chicken-and-egg problem is
hard to get around, although a study published in
June in JAMA Neurology tried. Researchers from
the Mayo Clinic in Rochester, Minn., examined
the medical records of 283 people older than 70.
None had dementia when they enrolled in the
Mayo Clinic Study of Aging. At the study’s start,
participants answered questions about their
sleep quality and received brain scans looking for
People who reported excessive daytime sleepiness — a telltale sign of fitful sleep — had more
plaques in their brains to start with. When
checked again about two years later, those same
people showed a more rapid accumulation than
people who slept soundly.
Other scientists have used brain scans to measure what happens to A-beta in people’s brains
after a sleepless night. Researchers from the
National Institutes of Health and colleagues
Hard day’s night
amyloid-beta in people
who were rested (top)
and then again after
31 hours without sleep
(bottom). In this PE T
scan of one volunteer’s
brain, levels of A-beta,
which is linked to
Alzheimer’s, rose in the
at arrow) after sleep
But sometimes, especially when